MiR-21 induced angiogenesis through AKT and ERK activation and HIF-1α expression.
MiR-21 induced angiogenesis through AKT and ERK activation and HIF-1α expression.
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DOI：
10.1371/journal.pone.0019139
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发表时间：
2011-04-22
期刊：
影响因子：
3.7
通讯作者：
Jiang BH
中科院分区：
文献类型：
--
作者：
Liu LZ;Li C;Chen Q;Jing Y;Carpenter R;Jiang Y;Kung HF;Lai L;Jiang BH
MicroRNAs(MiRNAs)是一种内源性的非编码小RNA，在多种细胞功能和肿瘤发展中发挥重要作用。最近的研究表明miR-21是与肿瘤生长和转移相关的重要miRNAs之一，但miR-21调控肿瘤血管生成的作用和分子机制尚不清楚。在本研究中，通过将前miR-21基因导入人前列腺癌细胞，获得了miR-21的高表达，并用鸡绒毛膜尿囊膜(CAM)检测肿瘤血管生成。我们发现在DU145细胞中过表达miR-21可以增加缺氧诱导因子-1α和血管内皮生长因子的表达，并诱导肿瘤血管生成。AKT和细胞外调节蛋白激酶(ERK)1/2被miR-21激活。抗肿瘤药对miR-21的抑制作用阻断了这一过程。MiR-21靶标PTEN的过表达也通过部分抑制AKT和ERK的活性以及减少HIF-1和VEGF的表达来抑制肿瘤血管生成。AKT和ERK抑制剂LY294002和U0126抑制缺氧诱导因子-1α和血管内皮生长因子的表达，并抑制血管生成。此外，单独抑制缺氧诱导因子-1α的表达可阻断miR-21诱导的肿瘤血管生成，表明缺氧诱导因子-1α是miR-21上调血管生成所必需的。因此，我们证明miR-21通过靶向PTEN诱导肿瘤血管生成，从而激活AKT和ERK1/2信号通路，从而增强HIF-1α和血管内皮生长因子的表达，HIF-1α是miR-21调控肿瘤血管生成的关键下游靶点。
MicroRNAs (miRNAs) are endogenous, small noncoding RNAs that play important roles in various cellular functions and tumor development. Recent studies have indicated that miR-21 is one of the important miRNAs associated with tumor growth and metastasis, but the role and molecular mechanism of miR-21 in regulating tumor angiogenesis remain to be elucidated. In this study, miR-21 was overexpressed by transfecting pre-miR-21 into human prostate cancer cells and tumor angiogenesis was assayed using chicken chorioallantoic membrane (CAM). We found that overexpression of miR-21 in DU145 cells increased the expression of HIF-1α and VEGF, and induced tumor angiogenesis. AKT and extracellular regulated kinases (ERK) 1/2 are activated by miR-21. Inhibition of miR-21 by the antigomir blocked this process. Overexpression of the miR-21 target, PTEN, also inhibited tumor angiogenesis by partially inactivating AKT and ERK and decreasing the expression of HIF-1 and VEGF. The AKT and ERK inhibitors, LY294002 and U0126, suppressed HIF-1α and VEGF expression and angiogenesis. Moreover, inhibition of HIF-1α expression alone abolished miR-21-inducing tumor angiogenesis, indicating that HIF-1α is required for miR-21-upregulated angiogenesis. Therefore, we demonstrate that miR-21 induces tumor angiogenesis through targeting PTEN, leading to activate AKT and ERK1/2 signaling pathways, and thereby enhancing HIF-1α and VEGF expression; HIF-1α is a key downstream target of miR-21 in regulating tumor angiogenesis.
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影响因子：
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作者：
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